Risk of thrombosis with thrombocytopenia syndrome after COVID‐19 vaccination prior to the recognition of vaccine‐induced thrombocytopenia and thrombosis: A self‐controlled case series study in England

Abstract Background Several studies have found increased risks of thrombosis with thrombocytopenia syndrome (TTS) following the ChAdOx1 vaccination. However, case ascertainment is often incomplete in large electronic health record (EHR)‐based studies. Objectives To assess for an association between clinically validated TTS and COVID‐19 vaccination. Methods We used the self‐controlled case series method to assess the risks of clinically validated acute TTS after a first COVID‐19 vaccine dose (BNT162b2 or ChAdOx1) or severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Case ascertainment was performed uninformed of vaccination status via a retrospective clinical review of hospital EHR systems, including active ascertainment of thrombocytopenia. Results One hundred seventy individuals were admitted to the hospital for a TTS event at the study sites between January 1 and March 31, 2021. A significant increased risk (relative incidence [RI], 5.67; 95% confidence interval [CI], 1.02‐31.38) of TTS 4 to 27 days after ChAdOx1 was observed in the youngest age group (18‐ to 39‐year‐olds). No other period had a significant increase, although for ChAdOx1 for all ages combined the RI was >1 in the 4‐ to 27‐ and 28‐ to 41‐day periods (RI, 1.52; 95% CI, 0.88‐2.63; and (RI, 1.70; 95% CI, 0.73‐3.8, respectively). There was no significant increased risk of TTS after BNT162b2 in any period. Increased risks of TTS following a positive SARS‐CoV‐2 test occurred across all age groups and exposure periods. Conclusions We demonstrate an increased risk of TTS in the 4 to 27 days following COVID‐19 vaccination, particularly for ChAdOx1. These risks were lower than following SARS‐CoV‐2 infection. An alternative vaccine may be preferable in younger age groups in whom the risk of postvaccine TTS is greatest.


Essentials
• Thrombosis with thrombocytopenia syndrome (TSS) may be induced by the COVID-19 vaccination.
• We used a retrospective clinical audit (complete case ascertainment) to assess this association.
• There is an increased risk of TTS in the short-term (4-27 days) following COVID-19 vaccination.
• The association is stronger in younger people vaccinated with the Oxford/AstraZeneca vaccine.

| BACKG ROUND AND R ATIONALE
Early clinical trials did not detect any major adverse effects from either of the first two COVID-19 vaccines used in the UK COVID-19 immunization program: ChAdOx1 nCov-19 (Oxford/AstraZeneca, Cambridge, England) and BNT162b2 mRNA (Pfizer/BioNTech, New York, NY, USA). 1,2 However, by March 10, 2021, the European Medicines Agency reported that 30 cases of thromboembolic events, which were predominantly venous, had been flagged among over 5 million ChAdOx1 recipients in Europe. 3 Subsequent reports defined an unusual postvaccination thrombosis with thrombocytopenia syndrome (TTS) 4 in multiple countries. [5][6][7][8] These reports have described a particular combination of thrombosis in unusual sites and thrombocytopenia occurring predominantly within 5 to 30 days after vaccination.
This combination of features has become widely known as vaccineinduced immune thrombocytopenia and thrombosis (VITT). 9 The United Kingdom's Medicines & Healthcare products and Regulatory Agency (MHRA) had received, as of September 29, 2021, 421 reports of major thromboembolic events with concurrent thrombocytopenia through its Yellow Card Scheme, after 41 million first doses and 38 million second doses of the ChAdOx1 vaccine. 5 The overall incidence after first or unknown doses was 15.1 per million doses. 5 The MHRA Yellow Card Scheme estimates derive from voluntary reporting, meaning cases may be misclassified as vaccine associated by the clinician based on guidelines and publicity at the time regarding any possible association. Indeed, the published UK experience of VITT recognizes 220 definite and probable cases over a similar time period. 10 However, multiple large population-based analyses have found increased risk of hematologic and vascular events that led to hospital admission or death in the weeks following first doses of the ChAdOx1 nCoV-19 in the United Kingdom [11][12][13] and Catalonia, 14 and higher than expected rates of cerebral venous sinus thrombo-

sis (CVST) in the ChAdOx1-vaccinated population in Denmark and
Norway. 3 These studies mainly used electronic health record (EHR) systems and therefore benefitted from higher power; however, their case ascertainment was reliant on the accuracy of coding of hospital diagnoses. This can be incomplete, as reported in a recent Scottish study that demonstrated that ascertainment of CVST from diagnostic codes on hospital discharge records had low sensitivity. 15 In this study, we investigate whether there is an increased risk of

Conclusions:
We demonstrate an increased risk of TTS in the 4 to 27 days following COVID-19 vaccination, particularly for ChAdOx1. These risks were lower than following SARS-CoV-2 infection. An alternative vaccine may be preferable in younger age groups in whom the risk of postvaccine TTS is greatest.

| Overview
We used the self-controlled case series (SCCS) method to assess the short-term risks of clinically validated acute TTS after a first COVID-19 vaccine dose (BNT162b2 or ChAdOx1, primary exposures) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (polymerase chain reaction-positive test, secondary exposure). Case ascertainment was performed manually by clinical hematologists uninformed of vaccination status via a retrospective clinical review of hospital EHR systems across four hospital sites in England.

| Case identification
All adults (aged >18 years) with an acute thrombotic event (venous or arterial thromboembolism) associated with a new-onset thrombocytopenia between January 1 and March 31, 2021, at four hospitals in England were identified. The case ascertainment process is outlined in Figure 1. Platelet counts were actively sought from all identified thrombosis cases to determine the specific syndrome of TTS among the most common occurrence of isolated thrombosis. We defined TTS as an acute thrombotic event (venous or arterial thrombosis) associated with a new-onset thrombocytopenia (platelet count <150 × 10 9 /L at presentation or within 5 days of hospital admission for a thrombotic event). We included all people aged ≥18 years at the time of the TTS event. We excluded any cases with symptom onset outside of the study period (January 1 to March 31, 2021), and any cases identified by the clinician as not having thrombocytopenia at presentation or within 5 days of hospital admission for the thrombotic event.
All identified cases were then linked to their vaccination status and SARS-CoV-2 testing history via the National Immunisation Management Service and Second Generation Surveillance System databases ( Figure 1). We constructed the vaccination status (unvac-

| Statistical methods
The SCCS method 16 was used to test the hypothesis of an increased risk of TTS in four risk periods of 4 to 13, 14 to 27, 28 to 41, and 4 to 27 days after COVID-19 vaccination and SARS-CoV-2-positive test, where day 0 is the day of vaccination or SARS-CoV-2 positive test, and day 1 the following calendar day, and so on. These risk periods were defined a priori based on early case reports of thrombosis with thrombocytopenia syndrome occurring predominantly within 5 to 30 days after vaccination. 4 In the SCCS method, cases act as their own controls as the incidence of the event in predefined risk periods following vaccination is compared to the incidence outside the risk period, generating a relative incidence (RI) measure automatically controlled for time-invariant confounding. 16 We investigated the risk associated with first COVID-19 vaccine dose (any manufacturer), first dose of  for the sensitivity analysis with the 28-day prevaccination low period included; however, inclusion of the 0 to 90 days following the first dose in follow-up attenuated the effect for the 4 to 27 days following ChAdOx1 (RI, 1.08; 95% CI, 0.45-2.57).

| Descriptive statistics and characteristics
Larger increased risks were observed following ChAdOx1 in the youngest age group (18-to 39-year-olds). None of this age group had received BNT162b2. An increased risk (RI, 5.67; 95% CI, 1.02-31.38) of TTS 4 to 27 days following ChAdOx1 was observed. The direction and size of risks were mixed in the 40-to 64-year-old and ≥65-year-old groups, and all had wide 95% CIs due to low sample size. Across all age groups, an increased but nonsignificant risk was observed for the 4-to 13-day period after vaccination with any COVID-19 vaccine.

| Relative incidence estimates -secondary exposure (SARS-CoV-2-positive test)
Sixteen   c Thrombosis admission date used as proxy for symptom onset date when unavailable (n = 1). If symptom onset date and admission date were unavailable, thrombosis diagnosis date was used as a proxy (n = 0). Cases with missing data for all three of these dates were excluded (n = 1).

| DISCUSS ION
Our study provides evidence of an increased risk of TTS 4 to 27 days after a first dose of ChAdOx1 in those aged 18 to 39 years old. In other age groups, point estimates were also >1 for ChadOx1 and any COVID-19 vaccine but were not statistically significant.
No increased risk following the first dose of BNT162b2 was observed. Overall, risks were multiple-fold higher in the exposure periods following a positive SARS-CoV-2 test than COVID-19 vaccination.
To our knowledge, this is the first study to use clinician-verified validation of TTS cases for cohort assembly to then investigate a potential association with COVID-19 vaccination. This laborintensive form of data collection enabled complete, robust case ascertainment in the source population. Importantly, platelet counts TA B L E 2 RIs and 95% CIs for an acute thrombotic event with thrombocytopenia in different time periods after COVID-19 vaccination and testing positive for SARS-CoV-2 using self-controlled case series analysis were ascertained for all thrombotic events, to identify the specific syndrome of TTS among the more common occurrence of isolated thrombosis. Once linked to vaccination data, this also enabled clini- The main limitation of our study is a lack of power-the timeintensive, manual nature of the data collection performed here meant that the geographical coverage and time frame for the study was small. Therefore, although the effect sizes provide evidence of TTS following ChAdOx1 vaccination, many of the RI point estimates are not statistically significant. We were also unable to convert the RIs into rates or estimates of attributable risk due to the lack of accurate data on the catchment populations of the hospital study sites; many are tertiary referral centers, and we therefore could not calculate a denominator. A recent UK-based study estimated the attrib-  18 highlighting the large difference in absolute risk between these age groups; generation of a similar absolute measure in our study would aid contextualization of the RIs. Inclusion of the 0 to 90 days following the first dose in the follow-up period attenuated after ChAdOx1 RI; this analysis has the advantage of not being affected by the event itself affecting subsequent vaccination (eg, due to death), but the disadvantage of having less power due to the limited control window. This demonstrates that there is some potential for bias when using the prevaccination person-time, and this is a study limitation. This study may underestimate rates of TTS in older people because our analysis is based on hospital admissions; fragile older people with symptoms of possible thrombosis, such as headache, after vaccination may not have necessarily been referred into a hospital before the syndrome of VITT was recognized.
Our results broadly echo those from similar studies. 11,12 A Scottish study of EHR data found that nested case-control effect sizes were larger than those estimated in the same cohort using SCCS, likely due to the presence of residual confounding or confounding by indication in the case-control study. 11 They detected an increased risk (relative risk [RR], 1.98; 95% CI, 1.29-3.02) of thrombocytopenia 0 to 28 days following ChAdOx1, but not for arterial thromboembolic events (RR, 0.97; 95% CI, 0.83-0.11). 11 Similar results were reported in an English SCCS analysis of risk of thrombocytopenia (incidence rate ratio [IRR], 1.33; 95% CI, 1.19-1.47) and venous thromboembolism (IRR, 1.10; 95% CI, 1.02-1.18) 8-14 days after ChAdOx1 vaccination. 12 The same study also found the risks of hematologic and vascular events to be substantially higher after SARS-CoV-2 infection than after vaccination. 12 These studies benefitted from higher power but are not directly comparable to ours due to using existing hospitalization discharge codes for outcome assignment, unlike our manual classification of cases as TTS.
In conclusion, we found some evidence of an increased risk of TTS in the time period 4 to 27 days following COVID-19 vaccination, particularly for ChAdOx1. However, the risk was much lower than following SARS-CoV-2 infection. Our findings suggest that in younger people, an alternative vaccine may be preferable and short-term monitoring of symptoms 4 to 27 days after vaccination are necessary. This supports the UK Joint Committee on Vaccine and Immunisation recommendation to preferentially use mRNA vaccines in people <40 years old given the ChAdOx1 risk-benefit profile in younger age groups. Similar studies using robust clinical case ascertainment of TTS over larger time frames and geographies are required to confirm our findings.

ACK N OWLED G M ENTS
The authors thank all the staff in the multiple departments at the hospital sites who helped in data collection.

R EL ATI O N S H I P D I SCLOS U R E
All authors declare no relevant conflicts of interest.

AUTH O R CO NTR I B UTI O N S
HH performed data cleaning, interpretation, and analysis, and wrote the report. CJA and BJH conceptualized and designed the study, helped in data interpretation, contributed to data collection, and helped refine and draft the report for important intellectual content.
NA and JS contributed to the design of the study, analysis, and interpretation of the data and revised the report critically for important intellectual content. GA and MR contributed to the conceptualization and design of the study and revised the report critically for